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TitleCryo-EM structures of Clostridium perfringens enterotoxin bound to its human receptor, claudin-4.
Journal, issue, pagesStructure, Vol. 32, Issue 11, Page 1936-11951.e5, Year 2024
Publish dateNov 7, 2024
AuthorsSewwandi S Rathnayake / Satchal K Erramilli / Anthony A Kossiakoff / Alex J Vecchio /
PubMed AbstractClostridium perfringens enterotoxin (CpE) causes prevalent and deadly gastrointestinal disorders. CpE binds to receptors called claudins on the apical surfaces of small intestinal epithelium. ...Clostridium perfringens enterotoxin (CpE) causes prevalent and deadly gastrointestinal disorders. CpE binds to receptors called claudins on the apical surfaces of small intestinal epithelium. Claudins normally regulate paracellular transport but are hijacked from doing so by CpE and are instead led to form claudin/CpE complexes. Claudin/CpE complexes are the building blocks of oligomeric β-barrel pores that penetrate the plasma membrane and induce gut cytotoxicity. Here, we present the structures of CpE in complex with its native claudin receptor in humans, claudin-4, using cryogenic electron microscopy. The structures reveal the architecture of the claudin/CpE complex, the residues used in binding, the orientation of CpE relative to the membrane, and CpE-induced changes to claudin-4. Further, structures and modeling allude to the biophysical procession from claudin/CpE complexes to cytotoxic β-barrel pores during pathogenesis. In full, this work proposes a model of claudin/CpE assembly and provides strategies to obstruct its formation to treat CpE diseases.
External linksStructure / PubMed:39383874 / PubMed Central
MethodsEM (single particle)
Resolution2.83 - 4.0 Å
Structure data

45748

9cmh

EMDB-45748, PDB-9cmh:
Cryo-EM structure of human claudin-4 complex with Clostridium perfringens enterotoxin
Method: EM (single particle) / Resolution: 4.0 Å

45749

9cmi

EMDB-45749, PDB-9cmi:
Cryo-EM structure of human claudin-4 complex with Clostridium perfringens enterotoxin, sFab COP-1, and Nanobody
Method: EM (single particle) / Resolution: 2.83 Å

Chemicals

ChemComp-AV0:
Lauryl Maltose Neopentyl Glycol

ChemComp-HOH:
WATER

Source
  • other entries (others)
  • homo sapiens (human)
  • clostridium perfringens (bacteria)
  • synthetic construct (others)
KeywordsMEMBRANE PROTEIN / claudin / enterotoxin / Fab / nanobody

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